Medicine's New Epicenter? Epigenetics

Flipping cancer's "off" switch.

BY LAURA BEIL

PUBLISHED TUESDAY, DECEMBER 9, 2008

Longtime cancer researcher Jean-Pierre Issa, MD, recalls the evening in May of 1992, when he sat in a San Diego hotel room leafing through the program for the American Association for Cancer Research annual conference. Among the thousands of presentations listed, he spotted only two that mentioned epigenetics. One of them was his.

These days, he’s not feeling so alone. In fact, the more research reveals about epigenetics, the more crowded the scientific gatherings get. Epigenetics is looking like it may become just as important—if not more so—than genetics itself in shaping the future of cancer treatment, diagnosis, and even prevention. It is, as one researcher wrote earlier this year, “at the epicenter of modern medicine.”

Not bad for a concept pushed to the margins of cancer research just a decade ago. “It’s something that was completely unexpected,” says Tanya Hoodbhoy, PhD, of the National Institutes of Health. “People thought genetics was it.”

Epigenetics isn’t new—the word first appeared in scientific circles decades ago. But the full appreciation of epigenetics didn’t begin to emerge until the 1990s at the height of excitement for the Human Genome Project, but epigenetics was simply outshone by its star counterpart. From 1989 to 2003 researchers undertook a historic endeavor to map the 20,000 or so genes that make people into people. The hope was to decode the genes, compare flawed genes with intact ones, and reveal secrets of human diseases such as cancer.

Yet, as researchers waded deeper into the study of human genes, the genetic coding of a malignant cell often turned out to be, by all appearances, normal. So what would make a cell with no mutations go so horribly awry? The problem wasn’t necessarily with the genes themselves. There had to be something else.

The human genome still retains its status as the blueprint for the body. But the epigenome—the way the genome is marked and packaged inside a cell’s nucleus—tells a cell which of the many sets of instructions on that blueprint to follow, which ones to ignore, and which ones to follow over and over again. If the genome is the blueprint, the epigenome is the contractor directing how the walls and windows are made, and whether the plumbing is correctly installed.

Because it has the power to switch our genes off and on, epigenetics is the reason that a skin cell doesn’t look or act like a liver cell, even though they both carry the same DNA. Epigenetics is the reason that identical twins, even though they are pretty much genetic clones of one another, don’t get the same diseases. And it is often the reason that a perfectly normal cell goes bad.

“When a group of investigators started talking about this in the early ’90s, there was considerable skepticism at the time,” says Issa, of M.D. Anderson Cancer Center in Houston.

The skepticism is all but gone. The National Institutes of Health announced earlier this year that $190 million had been set aside for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of heart disease, mental illness, and many other conditions. Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.

How do epigenetic changes occur? Research has established two main ways. In one, small chemical clusters called methyl groups attach to genes, as if they were charms hooking to a bracelet—a process called methylation. Most of the time, the charms silence the genes they connect to. In other words, the protein encoded by that gene is produced in much smaller amounts.

In the second method, epigenetics alters the way genes are bundled together. To squeeze several feet of genetic material inside the cell, DNA gets wound up like balls of twine. At the center of each ball are proteins called histones that allow the huge amount of DNA to be contained in a tightly wound chromosome structure. But this twine has messages written on it—the sequences of the genes—and the messages that the cell needs the most are wound more loosely, allowing for easier access and the production of proteins encoded by the gene. If the gene gets coiled too tightly around the histone, the cell can’t read it. This could lead to cancer if, for instance, this is the gene that helps keep cell growth under control. Or the twine could be too loose in the wrong place, allowing the cell to easily see a message that should be more concealed.

Epigenetic changes like methylation “by itself is not a good or bad process,” says Manel Esteller, MD, PhD, of the Spanish National Cancer Research Center in Madrid. It is part of the normal function of the cell. However, he says, too much or too little methylation can lead to problems. In other words, the methylation patterns might deactivate what are known as tumor suppressor genes that help protect a cell from cancer.

“I don’t think there will be a tumor type that would not involve an epigenetically inactivated tumor suppressor gene,” says Jirtle.